RESUMO
OBJECTIVES: To test whether HLA-DR4 acts in the mother, possibly during pregnancy, to contribute to the phenotype of autistic disorder in her fetus. DESIGN: Transmission disequilibrium testing in case mothers and maternal grandparents. SETTING: Previous studies have consistently shown increased frequency of HLA-DR4 in probands with autism and their mothers, but not their fathers. However, this has been documented only in case-control studies and not by a more direct study design to determine whether HLA-DR4 acts in mothers during pregnancy to contribute to autism in their affected offspring. PARTICIPANTS: We genotyped for HLA-DR alleles in members of 31 families with parents and maternal grandparents. Probands with autism were tested using the Autism Diagnostic Observation Schedule-Western Psychological Services and Autism Diagnostic Interview, Revised. There was 80% power to detect an odds ratio of 3.6. Participants were all families from New Jersey and were similar in number to earlier studies of autism and HLA-DR4. OUTCOME MEASURES: Analysis was by standard transmission disequilibrium testing. As a secondary test we examined the possibility of maternal imprinting. RESULTS: Significant transmission disequilibrium for HLA-DR4 was seen (odds ratio, 4.67; 95% confidence interval, 1.34-16.24; P = .008) for transmissions from maternal grandparents to mothers of probands, supporting a role for HLA-DR4 as an autism risk factor acting in mothers during pregnancy. Transmission disequilibrium was not seen for HLA-DR4 transmissions from parents to probands or from mothers to probands. CONCLUSIONS: The HLA-DR4 gene may act in mothers of children with autism during pregnancy to contribute to autism in their offspring. Further studies are required to confirm these findings.
Assuntos
Alelos , Transtorno Autístico/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Predisposição Genética para Doença/genética , Antígeno HLA-DR4/genética , Desequilíbrio de Ligação/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Transtorno Autístico/diagnóstico , Estudos de Casos e Controles , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Feminino , Frequência do Gene , Testes Genéticos , Impressão Genômica/genética , Genótipo , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Masculino , Razão de Chances , GravidezRESUMO
BACKGROUND: Certain loci on the human genome, such as glutathione S-transferase M1 (GSTM1), do not permit heterozygotes to be reliably determined by commonly used methods. Association of such a locus with a disease is therefore generally tested with a case-control design. When subjects have already been ascertained in a case-parent design however, the question arises as to whether the data can still be used to test disease association at such a locus. RESULTS: A likelihood ratio test was constructed that can be used with a case-parents design but has somewhat less power than a Pearson's chi-squared test that uses a case-control design. The test is illustrated on a novel dataset showing a genotype relative risk near 2 for the homozygous GSTM1 deletion genotype and autism. CONCLUSION: Although the case-control design will remain the mainstay for a locus with a deletion, the likelihood ratio test will be useful for such a locus analyzed as part of a larger case-parent study design. The likelihood ratio test has the advantage that it can incorporate complete and incomplete case-parent trios as well as independent cases and controls. Both analyses support (p = 0.046 for the proposed test, p = 0.028 for the case-control analysis) an association of the homozygous GSTM1 deletion genotype with autism.
